Project Summary I am an MD-PhD psychiatrist with the intertwined interests of understanding the neural basis of behavior and treating psychiatric patients. My goal is to become an expert on the circuit level mechanisms of neural transmission underlying stress, resilience and affective disorders. I plan to direct a research laboratory at an academic medical center, studying the neurophysiology of stress and affect, and have a small clinical practice. For my training, I moved to the New York State Psychiatric Institute (NYSPI). The NYSPI is the primary component of the Psychiatry Department of Columbia University, and is one of the largest mental health research facilities in the world. It has state-of-the-art facilities and a broad range of world-class scientists. At Columbia, I joined the laboratory of Dr. Joshua Gordon, an expert at studying circuits underlying psychiatric disorders. I also enlisted the mentorship of Dr. Eric Nestler, a pioneer in the field of chronic stress. With their guidance and this grant, I hope to accomplish 3 objectives: 1) Integrate in vivo circuit and behavioral analyses, 2) Learn to modulate circuits with optogenetics, 3) Develop as an independent physician-scientist. Depression is the leading cause of disease burden in the United States. Many patients never recover despite extensive treatment. Stress can precipitate depression yet some people are remarkably resilient in the face of adversity. Moreover, although women develop depression at nearly twice the rate of men, the vast majority of research on the physiology of stress susceptibility has been conducted in male subjects. Understanding how neural circuits function in susceptibility and resilience to stress is an exciting new approach to developing antidepressant treatment. The goal of my proposal is to identify how communication between the ventral tegmental area (VTA) and the nucleus accumbens (NAc), areas that process both reward and stress, contribute to susceptibility and resilience in males and females. The VTA-NAc circuit undergoes substantial molecular and electrical changes in mice that develop depression-like symptoms in response to stress. However, it remains unknown how these changes impact circuit communication. In Aim 1, I propose to record VTA-NAc circuit communication of susceptible and resilient male and female mice before, during and after undergoing chronic stress. Three different cell-types in the VTA project to the NAc and these projections may uniquely contribute to the development of susceptibility and resilience. In Aims 2 and 3, I propose to test if these projections are necessary or sufficient for susceptibility. Collectively, these experiments provide novel insight into how VTA-NAc circuit activity contributes to the development of susceptibility in males and females.